Oesophageal cancer represents less than 5% of all reported cancer cases, but ca. 30,000 new such cases are diagnosed per annum in the USA and the survival rate is low (see below). Oesophageal cancer can be divided into two major types, squamous cell carcinoma and adenocarcinoma, depending on the type of cells that are malignant. Barrett's oesophagus is a pre-malignant condition which is associated with an increased risk of development of oesophageal cancer; especially adenocarcinoma [Kiesslich et al, Clin. Gastroenterol. Hepatol., 4, 979-987 (2006)]. Chronic reflux increases risk for Barrett's oesophagus, and it has therefore been suggested that gastro oesophageal reflux (GERD) is a risk factor for oesophageal cancer.
Adenocarcinoma of the oesophagus is more prevalent than squamous cell carcinoma in the USA and Western Europe. Oesophageal cancer can be a treatable disease but is rarely curable. The overall 5-year survival rate is between 5% and 30%. Early diagnosis of oesophageal cancer improves the survival rate of the patient. Primary treatment includes surgery alone or chemotherapy in combination with radiation. Chemotherapy used in treatment of oesophageal cancer includes 5-fluorouracil and cisplatin. Lack of precise pre-operative staging is a major clinical problem.
The presence of low grade dysplasia (i.e. abnormal tissue growth) in Barrett's oesophagus is a risk factor for the development of oesophageal cancer, but surveillance currently relies on histopathology [Lim et al, Endoscopy, 39, 581-7 (2007)]. Diagnosis of dysplasia in Barrett's oesophagus is currently via random four-quadrant biopsies every 1 to 2 cm (the Seattle protocol), which is time-consuming and costly [DaCosta et al, Best Pract. Res. Clin. Gastroenterol., 20(1), 41-57 (2006)]. Dysplasia in Barrett's oesophagus is not normally visible during routine endoscopy [Endlicher et al, Gut, 48, 314-319 (2001)].
U.S. Pat. No. 6,035,229 (Washington Research Foundation) describes a system for detecting Barrett's oesophagus utilizing an illumination and imaging probe at the end of a catheter. The document does not disclose an optical contrast agent.
Staining of Barrett's oesophagus tissue in vivo has been compared with staining of biopsy samples in vitro, using the dye methylene blue in the detection of highly dysplastic or malignant tissue [Canto at al, Endoscopy, 33, 391-400 (2001)].
Kiesslich at al [Clin. Gastroenterol, Hepatol., 4, 979-987 (2006)] reported on the use of fluorescein to aid the detection of Barrett's epithelium and associated neoplasia using confocal laser endomicroscopy.
WO 2005/058371 discloses optical imaging contrast agents for imaging of oesophageal cancer and Barrett's oesophagus in vivo. The contrast agents have an affinity for a biological target which is abnormally expressed in Barrett's oesophagus.
The contrast agents of WO 2005/058371 are preferably of formula:V-L-R                where:        V is one or more vector moieties having affinity for an abnormally expressed target in oesophageal cancer or Barrett's oesophagus;        L is a linker moiety or a bond; and        R is one or more reporter moieties detectable in optical imaging.        
A wide range of targets is described, but the target is preferably selected from E-cadherin, CD44, P62/c-myc (HGF receptor), p53 and EGFR/erB-2. The vector (V) is stated to be preferably selected from peptides, peptoid moieties, oligonucleotides, oligosaccharides, fat-related compounds and traditional organic drug-like small molecules. The reporter (R) is preferably a dye that interacts with light in the wavelength region from the ultraviolet to the near-infrared part of the electromagnetic spectrum.
Barrett's Oesophagus is a condition characterised by replacement of squamous oesophageal epithelium with columnar epithelium (metaplasia). A proportion of Barrett's Oesophagus patients will develop oesophageal adenocarcinoma, and the critical step in this process is the formation of dysplasia. Therefore patients diagnosed with dysplasia undergo therapy which can include anti-reflux medication, endoscopic mucosal ablation and surgical resection, depending on the severity of the disease (FIG. 1; summarised from “Guidelines for the Diagnosis and Management of Barrett's Columnar-lined Oesophagus”, UK Society of Gastroenterology, August 2005; www.bsg.org.uk):
Treated patients are followed up at 6 monthly intervals to assess response to therapy. Responders (i.e. patients where the evidence is that the therapy is being effective), are treated as low-risk patients, while continued/additional treatment is considered for non-responders. There is a need for better therapy selection, especially among Barrett's Oesophagus patients that do not respond to first-line treatment, since more target specific therapies are being developed.
The Present Invention.
The present invention relates to a method to assist in the determination of therapy for a patient suffering from Barrett's oesophagus. The method comprises the use of an imaging agent comprising a vector which targets (a) Her2, (b) cMet, (c) guanylyl cyclase or (d) IGF1R. The method provides a therapy selection tool, of particular value for patients that do not respond to first-line treatment. Patients that are shown to strongly express one of these markers in the diseased tissue are expected to benefit from therapies which targeting those cellular proteins (FIG. 2).
The present invention provides evidence that cMet, Her2, IGF1-R and guanylyl cyclase c expression increases in subpopulations of Barrett's patients. Hence, identification of such patients using suitable imaging agents targeted to these proteins would allow those subpopulations to benefit from cMet, Her2, IGF1-R or guanylyl cyclase c targeted drug therapies, and at the same time enable more effective use of therapy resources.